This K08 proposal describes a five-year research and training plan that will facilitate the transition of Krithika Lingappan, M.D., to an independent academic researcher in the field of neonatal lung injury. Dr. Lingappan has a strong background in basic science, and completed her training in neonatology at Baylor College of Medicine (BCM), where she is now a tenure-track assistant professor. Her overarching research goal is to delineate the mechanisms of sex-specific differences in neonatal hyperoxic lung injury. Dr. Lingappan is working towards a Ph.D. degree in BCM's Clinical Scientist Training Program. Her primary mentor is Bhagavatula Moorthy, Ph.D., Professor of Pediatrics at BCM, who is a well-funded researcher in the field of hyperoxic lung injury, ARDS and cytochrome P450 and has a highly successful track record of mentoring. She has also assembled an advisory committee of four outstanding translational researchers to aid in her research and career development. Dr. Lingappan has taken biostatistics and research design courses and completed preliminary studies. She will take additional courses relevant to her career goal and research plan, with the understanding that completion of the research aims will require intimate knowledge of 1) manipulation of mouse models of experimental bronchopulmonary dysplasia and assessment of lung injury and lung development; 2) established and emerging techniques in molecular biology; 3) bioinformatics and systems biology approach to diseases; and 4) sex/gender oriented research. Dr. Lingappan's immediate goals are to: 1) Improve her knowledge and acquire new skills in the area of neonatal hyperoxic lung injury. 2) Develop skill sets in bioinformatics and systems biology approach to diseases. 3) Build on her knowledge of the role of cytochrome P450 system and investigate its role in sex- specific differences in neonatal hyperoxic lung injury. 4) Develop a deeper understanding of sex-hormone dependent and independent mechanisms responsible for sexual dimorphism in neonatal outcomes. 5) Generate data leading to peer reviewed publications and presentations in national meetings and to prepare a strong, hypothesis-driven proposal to study the specific genes and pathways responsible for sexual dimorphism in bronchopulmonary dysplasia, leading to an R01 application. The long-term goal is to attain the skills, knowledge and experience needed to become a successful academic physician-scientist with independent research and funding in the area of neonatal hyperoxic lung injury and mechanisms behind sex- specific outcomes in neonatal-perinatal medicine. The training opportunities and resources at Baylor College of Medicine, in the world-renowned Texas Medical Center in Houston, provide an ideal environment for Dr. Lingappan's career development program. She will continue to have at least 75% protected time to devote to the activities described in this proposal. Her training and research plan incorporate a combination of coursework, directed reading, mentoring, hands-on research experience, presentations at national and regional scientific meetings, preparation of manuscripts and an R01 application. Research: Male sex is considered an independent predictor for the development of bronchopulmonary dysplasia. The cytochrome P450 (CYP)1A family of proteins are protective against hyperoxic lung injury, and sex-specific differences in the expression of CYP1A are known under hyperoxia, with higher levels in females. Androgens are known to delay lung maturation and are detrimental in acute lung injury animal models. The reasons underlying sexually dimorphic outcomes in premature neonates are not known, and a focused investigation of the effect of sex/gender on hyperoxic lung injury and the underlying mechanisms has not been attempted.
The specific aims of the project are to: 1. compare lung injury between male and female neonatal mice after postnatal hyperoxia exposure and elucidate the underlying molecular mechanism(s), 2. determine the mechanistic role of cytochrome P50 1A enzymes in the sex-specific differences in neonatal hyperoxic lung injury, and 3. elucidate the effect of androgens on sex-specific differences in neonatal hyperoxic lung injury. Understanding the basis of the sex-based differences is important in order to develop new approaches and individualized therapeutic options for the prevention, diagnosis, and treatment of BPD. The research described in this proposal is innovative, feasible to be completed within the award period, and of high potential significance. This research will be a substantive addition to the knowledge gap and will advance the field of neonatal hyperoxic lung injury and will serve as a vehicle for the advancement of Dr. Lingappan's career as an independent investigator.
Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. Understanding the molecular basis of sex-specific differences, as proposed in this application, will lead to the development of novel approaches and individualized therapeutic options for BPD.
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